Chromosomal translocations involving the MLL1 gene characterize a poor prognosis subset of acute myeloid leukemia (AML), referred to as 11q23-AML. Transcription of the HOXA9 and HOXA10 genes is enhanced in hematopoietic stem and progenitor cells in these leukemias. We previously found the ARIH2 gene was repressed by HoxA9 in myeloid progenitors, but activated by HoxA10 during granulopoiesis. ARIH2 encodes the Triad1 protein, an anti-proliferative E3 ubiquitin ligase. In the current study, we investigate the role of Triad1 in leukemogenesis induced by an MLL1 fusion protein (Mll-Ell). We found Mll-Ell increased expression of HoxA9, HoxA10, and Triad1 because HoxA9 represses only one of two ARIH2 cis elements that are activated by HoxA10. Although Triad1 antagonized the generally pro-proliferative effects of the Mll-Ell oncoprotein, we found blocking HoxA9 and HoxA10 phosphorylation shifted the balance to ARIH2 repression in Mll-Ell+ cells. We investigated the significance of these in vitro results in a murine bone marrow transplant model. We found Triad1 knockdown significantly shortened the latency to development of AML in mice transplanted with Mll-Ell-transduced bone marrow. And, Triad1 expression fell during the prolonged AML latency period in mice transplanted with bone marrow expressing Mll-Ell alone. Our studies identify Triad1 as a leukemia suppressor in 11q23-AML. This suggests defining relevant Triad1 substrates may indicate novel therapeutic targets in this disease.

中文翻译：

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E3泛素连接酶Triad1影响Mll-Ell诱导的急性髓细胞性白血病的发展。

涉及MLL1基因的染色体易位是急性髓性白血病（AML）的不良预后亚群，称为11q23-AML。在这些白血病的造血干细胞和祖细胞中，HOXA9和HOXA10基因的转录增强。我们先前发现ARIH2基因在髓样祖细胞中被HoxA9抑制，但在粒细胞生成过程中被HoxA10激活。ARIH2编码Triad1蛋白，一种抗增殖的E3泛素连接酶。在当前的研究中，我们调查Triad1在由MLL1融合蛋白（Mll-Ell）诱导的白血病发生中的作用。我们发现Mll-Ell增加了HoxA9，HoxA10和Triad1的表达，因为HoxA9仅抑制HoxA10激活的两个ARIH2顺式元件之一。尽管Triad1拮抗了Mll-Ell癌蛋白的普遍促增殖作用，我们发现阻断HoxA9和HoxA10磷酸化将平衡转移至Mll-Ell +细胞中的ARIH2抑制。我们在小鼠骨髓移植模型中研究了这些体外结果的重要性。我们发现，Triad1敲低显着缩短了Mll-Ell转导的骨髓移植小鼠中AML发育的潜伏期。并且，在延长了AML潜伏期的小鼠中，Triad1表达下降，该小鼠移植了单独表达Mll-Ell的骨髓。我们的研究确定Triad1是11q23-AML中的白血病抑制因子。这表明定义相关的Triad1底物可能表明该疾病的新治疗靶标。我们发现，Triad1敲低显着缩短了Mll-Ell转导的骨髓移植小鼠中AML发育的潜伏期。并且，在延长了AML潜伏期的小鼠中，Triad1表达下降，该小鼠移植了单独表达Mll-Ell的骨髓。我们的研究确定Triad1是11q23-AML中的白血病抑制因子。这表明确定相关的Triad1底物可能表明该疾病具有新的治疗靶标。我们发现，Triad1敲低显着缩短了Mll-Ell转导的骨髓移植小鼠中AML发育的潜伏期。并且，在延长了AML潜伏期的小鼠中，Triad1表达下降，该小鼠移植了单独表达Mll-Ell的骨髓。我们的研究确定Triad1是11q23-AML中的白血病抑制因子。这表明确定相关的Triad1底物可能表明该疾病具有新的治疗靶标。